Time and money and advancing stem cell research

The human genome

Way back in the 1990’s scientists were hard at work decoding the human genome, trying to map and understand all the genes that make up people. At the time there was a sense of hope, a feeling that once we had decoded the genome, we’d have cures for all sorts of things by next Thursday. It didn’t quite turn out that way.

The same was true for stem cell research. In the early days there was a strong feeling that this was going to quite quickly produce new treatments and cures for diseases ranging from Parkinson’s and Alzheimer’s to heart disease and stroke. Although we have made tremendous strides we are still not where we hoped we’d be.

It’s a tough lesson to learn, but an important one: good scientific research moves at its own pace and pays little heed to our hopes or desires. It takes time, often a long time, and money, usually a lot of money, to develop new treatments for deadly diseases and disorders.

Many people, particularly those battling deadly diseases who are running out of time, are frustrated at the slow pace of stem cell research, at the years and years of work that it takes to get even the most promising therapy into a clinical trial where it can be tested in people. That’s understandable. If your life is on the line, it’s difficult to be told that you have to be patient. Time is a luxury many patients don’t have.

But that caution is necessary. The last thing we want to do is rush to test something in people that isn’t ready. And stem cells are a whole new way of treating disease, using cells that may stay in the body for years, so we really need to be sure we have done everything we can to ensure they are safe before delivering them to people.

The field of gene therapy was set back years after one young patient, Jesse Gelsinger, died as a result of an early experimental treatment. We don’t want the same to happen to stem cell research.

And yet progress is being made, albeit not as quickly as any of us would like. At the end of the first ten years of CIRM’s existence we had ten projects that we supported that were either in, or applying to be in, a clinical trial sanctioned by the US Food and Drug Administration (FDA). Five years later that number is 56.

Most of those are in Phase 1 or 2 clinical trials which means they are still trying to show they are both safe and effective enough to be made available to a wider group of people. However, some of our projects are in Phase 3, the last step before, hopefully, being given FDA approval to be made more widely available and – just as important – to be covered by insurance.

Other CIRM-funded projects have been given Regenerative Medicine Advanced Therapy (RMAT) designation by the FDA, a new program that allows projects that show they are safe and benefit patients in early stage clinical trials, to apply for priority review, meaning they could get approved faster than normal. Out of 40 RMAT designations awarded so far, six are for CIRM projects.

We are working hard to live up to our mission statement of accelerating stem cell treatments to patients with unmet medical needs. We have been fortunate in having $3 billion to spend on advancing this research in California; an amount no other US state, indeed few other countries, have been able to match. Yet even that amount is tiny compared to the impact that many of these diseases have. For example, the economic cost of treating diabetes in the US is a staggering $327 billion a year.

The simple truth is that unless we, as a nation, invest much more in scientific research, we are not going to be able to develop cures and new, more effective, treatments for a wide range of diseases.

Time and money are always going to be challenging when it comes to advancing stem cell research and bringing treatments to patients. With greater knowledge and understanding of stem cells and how best to use them we can speed up the timeline. But without money none of that can happen.

Our blog is just one of many covering the topic of “What are the hurdles impacting patient access to cell and gene therapies as part of Signal’s fourth annual blog carnival.

CIRM-Funded Researchers Develop Chimeric “Mighty Mouse” Model to Study Alzheimer’s Disease

Dr. Mathew Blurton-Jones, leader of team that developed the chimeric “Mighty Mouse” model at the University of California, Irvine

In ancient Greek mythology, a Chimera was a creature that was usually depicted as a lion with an additional goat head and a serpent for a tail. Due to the Chimera’s animal hybrid nature, the term “chimeric” came to fruition in the scientific community as a way to describe an organism containing two or more different sets of DNA.

A CIRM-funded study conducted by Dr. Mathew Blurton-Jones and his team at UC Irvine describes a way for human brain immune cells, known as microglia, to grow and function inside mice. Since the mice contain a both human cells and their own mice cells, they are described as being chimeric.

In order to develop this chimeric “mighty mouse” model, Dr. Blurton-Jones and his team generated induced pluripotent stem cells (iPSCs), which have the ability to turn into any kind of cell, from cell samples donated by adult patients. For this study, the researchers converted iPSCs into microglia, a type of immune cell found in the brain, and implanted them into genetically modified mice. After a few months, they found that the implanted cells successfully integrated inside the brains of the mice.

By finding a way to look at human microglia grow and function in real time in an animal model, scientists can further analyze crucial mechanisms contributing to neurological conditions such as Alzheimer’s, Parkinson’s, traumatic brain injury, and stroke.

For this particular study, Dr. Blurton-Jones and his team looked at human microglia in the mouse brain in relation to Alzheimer’s, which could hold clues to better understand and treat the disease. The team did this by introducing amyloid plaques, protein fragments in the brain that accumulate in people with Alzheimer’s, and evaluating how the human microglia responded. They found that the human microglia migrated toward the amyloid plaques and surrounding them, which is what is observed in Alzheimer’s patients.

In a press release, Dr. Blurton-Jones expressed the importance of studying microglia by stating that,

“Microglia are now seen as having a crucial role in the development and progression of Alzheimer’s. The functions of our cells are influenced by which genes are turned on or off. Recent research has identified over 40 different genes with links to Alzheimer’s and the majority of these are switched on in microglia. However, so far we’ve only been able to study human microglia at the end stage of Alzheimer’s in post-mortem tissues or in petri dishes.”

Furthermore, Dr. Blurton-Jones highlighted the importance of looking at human microglia in particular by saying that,

“The human microglia also showed significant genetic differences from the rodent version in their response to the plaques, demonstrating how important it is to study the human form of these cell.”

The full results of this study were published in Cell.

Advancing stem cell research in many ways

Speakers at the Alpha Stem Cell Clinics Network Symposium: Photo by Marco Sanchez

From Day One CIRM’s goal has been to advance stem cell research in California. We don’t do that just by funding the most promising research -though the 51 clinical trials we have funded to date clearly shows we do that rather well – but also by trying to bring the best minds in the field together to overcome problems.

Over the years we have held conferences, workshops and symposiums on everything from Parkinson’s disease, cerebral palsy and tissue engineering. Each one attracted the key players and stakeholders in the field, brainstorming ideas to get past obstacles and to explore new ways of developing therapies. It’s an attempt to get scientists, who would normally be rivals or competitors, to collaborate and partner together in finding the best way forward.

It’s not easy to do, and the results are not always obvious right away, but it is essential if we hope to live up to our mission of accelerating stem cell therapies to patients with unmet medical needs.

For example. This past week we helped organize two big events and were participants in another.

The first event we pulled together, in partnership with Cedars-Sinai Medical Center, was a workshop called “Brainstorm Neurodegeneration”. It brought together leaders in stem cell research, genomics, big data, patient advocacy and the Food and Drug Administration (FDA) to tackle some of the issues that have hampered progress in finding treatments for things like Parkinson’s, Alzheimer’s, ALS and Huntington’s disease.

We rather ambitiously subtitled the workshop “a cutting-edge meeting to disrupt the field” and while the two days of discussions didn’t resolve all the problems facing us it did produce some fascinating ideas and some tantalizing glimpses at ways to advance the field.

Alpha Stem Cell Clinics Network Symposium: Photo by Marco Sanchez

Two days later we partnered with UC San Francisco to host the Fourth Annual CIRM Alpha Stem Cell Clinics Network Symposium. This brought together the scientists who develop therapies, the doctors and nurses who deliver them, and the patients who are in need of them. The theme was “The Past, Present & Future of Regenerative Medicine” and included both a look at the initial discoveries in gene therapy that led us to where we are now as well as a look to the future when cellular therapies, we believe, will become a routine option for patients. 

Bringing these different groups together is important for us. We feel each has a key role to play in moving these projects and out of the lab and into clinical trials and that it is only by working together that they can succeed in producing the treatments and cures patients so desperately need.

Cierra Jackson: Photo by Marco Sanchez

As always it was the patients who surprised us. One, Cierra Danielle Jackson, talked about what it was like to be cured of her sickle cell disease. I think it’s fair to say that most in the audience expected Cierra to talk about her delight at no longer having the crippling and life-threatening condition. And she did. But she also talked about how hard it was adjusting to this new reality.

Cierra said sickle cell disease had been a part of her life for all her life, it shaped her daily life and her relationships with her family and many others. So, to suddenly have that no longer be a part of her caused a kind of identity crisis. Who was she now that she was no longer someone with sickle cell disease?

She talked about how people with most diseases were normal before they got sick, and will be normal after they are cured. But for people with sickle cell, being sick is all they have known. That was their normal. And now they have to adjust to a new normal.

It was a powerful reminder to everyone that in developing new treatments we have to consider the whole person, their psychological and emotional sides as well as the physical.

CIRM’s Dr. Maria Millan (right) at a panel presentation at the Stanford Drug Discovery Symposium. Panel from left to right are: James Doroshow, NCI; Sandy Weill, former CEO Citigroup; Allan Jones, CEO Allen Institute

And so on to the third event we were part of, the Stanford Drug Discovery Symposium. This was a high level, invitation-only scientific meeting that included some heavy hitters – such as Nobel Prize winners Paul Berg and  Randy Schekman, former FDA Commissioner Robert Califf. Over the course of two days they examined the role that philanthropy plays in advancing research, the increasingly important role of immunotherapy in battling diseases like cancer and how tools such as artificial intelligence and big data are shaping the future.

CIRM’s President and CEO, Dr. Maria Millan, was one of those invited to speak and she talked about how California’s investment in stem cell research is delivering Something Better than Hope – which by a happy coincidence is the title of our 2018 Annual Report. She highlighted some of the 51 clinical trials we have funded, and the lives that have been changed and saved by this research.

The presentations at these conferences and workshops are important, but so too are the conversations that happen outside the auditorium, over lunch or at coffee. Many great collaborations have happened when scientists get a chance to share ideas, or when researchers talk to patients about their ideas for a successful clinical trial.

It’s amazing what happens when you bring people together who might otherwise never have met. The ideas they come up with can change the world.

Media shine a spotlight on dodgy stem cell clinics

A doctor collects fat from a patient’’s back as part of an experimental stem cell procedure in Beverly Hills, Calif. on Dec. 5, 2014. (Raquel Maria Dillon / Associated Press)

For several years now, we have been trying to raise awareness about the risks posed by clinics offering unproven or unapproved stem cell therapies. At times it felt as if we were yelling into the wind, that few people were listening. But that’s slowly changing. A growing number of TV stations and newspapers are picking up the message and warning their readers and viewers. It’s a warning that is getting national exposure.

Why are we concerned about these clinics? Well, they claim their therapies, which usually involve the patient’s own fat or blood cells, can cure everything from arthritis to Alzheimer’s. However, they offer no scientific proof, have no studies to back up their claims and charge patients thousands, sometimes tens of thousands of dollars.

In the LA Times, for example, reporter Usha Lee McFarling, wrote an article headline “California has gone crazy for sketchy stem cell treatments”. In it she writes about the claims made by these clinics and the dangers they pose:

“If it sounds too good to be true, it is. There is no good scientific evidence the pricey treatments work, and there is growing evidence that some are dangerous, causing blindness, tumors and paralysis. Medical associations, the federal government and even Consumer Reports have all issued stern warnings to patients about the clinics.”

In Denver, the ABC TV station recently did an in-depth interview with a local doctor who is trying to get Colorado state legislators to take legal action against stem cell clinics making these kinds of unsupported claims.

Chris Centeno of the Centeno-Schultz Clinic, who’s specialized in regenerative medicine and research for more than a decade, said too many people are simply being scammed.

“It’s really out of control,” he told the station.

ABC7 did a series of reports last year on the problem and that may be prompting this push for a law warning consumers about the dangers posed by these unregulated treatments which are advertised heavily online, on TV and in print.

In California there is already one law on the books attempting to warn consumers about these clinics. CIRM worked with State Senator Ed Hernandez to get that passed (you can read about that here) and we are continuing to support even stronger measures.

And the NBC TV station in San Diego recently reported on the rise of stem cell clinics around the US, a story that was picked up by the networks and run on the NBC Today Show.

One of the critical elements in helping raise awareness about the issue has been the work done by Paul Knoepfler and Leigh Turner in identifying how many of these clinics there are around the US. Their report, published in the journal Cell Stem Cell, was the first to show how big the problem is. It attracted national attention and triggered many of the reports that followed.

It is clear momentum is building and we hope to build on that even further. Obviously, the best solution would be to have the Food and Drug Administration (FDA) crack down on these clinics, and in some cases they have. But the FDA lacks the manpower to tackle all of them.

That’s where the role of the media is so important. By doing stories like these and raising awareness about the risks these clinics pose they can hopefully help many patients avoid treatments that will do little except make a dent in their pocket.

The Sad Lane: How I navigated one of the happiest times of my life while my mom was losing hers to Alzheimer’s

In 1983 President Ronald Reagan named November as Alzheimer’s Awareness month, to raise awareness about the growing impact the disease was having on Americans. At the time there were less than two million people with the disease. Today that number has grown to more than five million and is expected to reach 16 million by the year 2050. There is no cure and no effective treatments.

To mark Alzheimer’s Awareness month we are reprinting an article that CIRM Board member and Patient Advocate for Alzheimer’s, Lauren Miller, wrote for Lenny magazine, charting her own personal journey with the disease.

The Sad Lane

Stem Cell Roundup: Clinical Trial on the Horizon for Parkinson’s Disease, New Probe Targets Tricky Cancer Cells – Rare Brain Disease May Be Key to Alzheimer’s Insights

Stem Cell Image of the Week: This week’s image shows dopamine producing brain cells. These are the cells that are depleted in people with Parkinson’s Disease.

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Photo courtesy of B. Bick, . Poindexter, UT Med. School/SPL

Parkinson’s disease news: a new clinical trial, a new face of the disease  (Kevin McCormack)

In his long and illustrious career Alan Alda has worn many hats. First as the star of the hit TV show “M*A*S*H” (the season finale of that is still the most watched TV show ever), then as a writer, director and movie star and, more recently, as the face of popular science and science communications. This week Alda revealed that he has Parkinson’s disease (PD).

In a post on Twitter he said:

“I have decided to let people know I have Parkinson’s to encourage others to take action. I was Diagnosed 3 and a half years ago, but my life is full. I act, I give talks, I do my podcast, which I love. If you get a diagnosis, keep moving!”

CIRM Board member David Higgins echoed those sentiments in an interview on KUSI TV News, San Diego. Dr. Higgins is the patient advocate member for Parkinson’s on the Board, and was diagnosed with PD in 2011, he says being active physically and intellectually are important in helping cope with PD and leading a normal life.

There was also some encouraging news about PD on the research front. Scientists in Japan are about to start a clinical trial using iPSCs to treat people with PD. The cells are created by taking blood stem cells from healthy donors and turning them into dopaminergic progenitors, precursors to the kind of cell destroyed by PD. The cells will then be transplanted into the brains of seven patients with PD.

The researchers, from Kyoto University, say previous studies show the cells could survive in monkeys for up to two years and help improve symptoms of Parkinson’s disease in the primates.

New Molecular Probe Targets Elusive Cancer Stem Cells in Mice (Adonica Shaw)

180802 cancer cells

A group of researchers at the University of Illinois made an advance in how we treat cancer patients this week. In a paper, published in the journal ACS Central Science, the researchers described a new and more effective way of identifying cancer stem cells in cultures of multiple human cancer cell lines as well as in live mice.

After a primary tumor is treated, cancer stem cells may still lurk in the body, ready to metastasize and cause a recurrence of the cancer in a form that’s more aggressive and resistant to treatment. The researchers developed a molecular probe that seeks out these elusive cells and lights them up so they can be identified, tracked and studied not only in cell cultures, but in their native environment: the body.

While other commercial agents are available to flag cancer stem cells, their application is limited, Chan said. Some cannot distinguish between live and dead cells, others can mistakenly bind to wrong targets. The most popular – antibodies that seek out markers on the cell’s surface – are specific to cell types and their large size can prevent them from reaching the small spaces where cancer stem cells tend to lurk. All are designed for use in cell cultures or artificial tumor environments, which lack the complexity of the whole body, Chan said.

In contrast, their new probe, called AlDeSense, is a small molecule that binds to an enzyme related to the property of stemness in cancer cells. The probe becomes activated, emitting a fluorescent signal only when it reacts with the target enzyme – which cancer stem cells produce in high concentrations.

In a series of experiments, the group found that the enzyme seems to be a marker of stemness across many types of cancer, indicating that AlDeSense may be broadly applicable for clinical imaging.

The researchers demonstrated that AlDeSense is compatible with two major cellular techniques – flow cytometry and confocal imaging.

The ability to find and track cancer stem cells in the body, as well as their state of stemness – the signal decreases as the cells differentiate – allowed the researchers to follow cells from injection to tumor as they spread through the bodies of the mice, answering some fundamental questions of how cancer stem cells behave.

According to the researchers nobody knew what happens between injection of cancer stem cells and removal of a tumor prior to this study. There are a lot of models that hypothesize about how cancer stem cells differentiate and grow, but limited experimental data exists.

Through their study, they saw the stemness properties are maintained in the population, even after they metastasize. There’s something about the environment in the body that supports stem cell characteristics. With AlDeSense, now they can profile that environment.

Since they know that the probe only interacts with that one target, they can use the probe to look for a drug that can inhibit this enzyme and verify it in cells and in live animals. The group is currently pursuing a screening for inhibitors or drugs that can kill cancer stem cells by targeting this enzyme.

Tackling a Rare Brain Disease May Also Lead to Alzheimer’s Insights (Todd Dubnicoff)

Alzheimer’s disease and ALS are very complex neurodegenerative disorders, making it very difficult for researchers to tease out the underlying causes let alone find treatments. To make inroads into a better understanding of these incurable diseases, scientists at City of Hope decided to first tackle a related, yet relatively more simple, nervous system disorder called Alexander disease. And this week, the strategy paid off with newly published research in Cell Stem Cell, funded in part by CIRM, describing the development of a patient-derived stem cell model system that could help evaluate novel treatments for all of these neurodegenerative diseases.

AlexanderDisease

An Alexander disease patient's stem cell-derived astrocytes (green) inhibits the growth of precursor cells that, in healthy patients, becomes myelin and speed up the brain's communication network. Credit: Yanhong Shi/City of Hope

The team generated astrocytes, a type of nervous system cell, using induced pluripotent stem cells derived from Alexander disease patients. It was previously known that the mutation in Alexander disease causes the patient’s astrocytes to block another cell type’s ability to produce myelin, the protective covering over neurons that’s critical for communication between nerve cells. But it wasn’t clear how this inhibition happened. In this study, the team found a possible culprit, a protein called CHI3L1 that’s secreted by the patient-derived astrocytes (but not by those from healthy individuals) and interferes with myelin production. So, finding drugs that target CHI3L1 could lead to therapies for Alexander disease.

Dysfunctional astrocytes have also been implicated in ALS and Alzheimer’s disease. So, using this newly developed model system for studying astrocytes could lead to new therapeutic strategies. In a press release, team leader Dr. Yanhong Shi, PhD, provides a specific example how this could work:

“The bulk of ApoE4 resides in astrocytes; ApoE4 is a gene variant known for increasing the risk of Alzheimer’s disease. So, if we understand how astrocytes function, then we can develop therapies to treat Alexander disease and perhaps other diseases that involve astrocytes, such as Alzheimer’s and ALS.”

Promising Advances in Alzheimer’s Research Could Create More Advanced Therapy Options

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Photo Courtesy of NIH

New developments in Alzheimer’s research are bringing us closer to more precise therapies for this debilitating disease.

Alzheimer’s disease, is characterized by the formation of amyloid plaques in the brain, which interfere with the normal communication flow between brain cells, leading to debilitating symptoms like memory loss and impaired decision-making. These plaques are made out of beta-amyloid proteins that stick together.

Over the past few years, researchers from several institutions have been working to develop antibodies that bind to and neutralize the toxic effects of the beta-amyloid. The search for effective antibodies, although promising, has been riddled with setbacks. Knowing this, a team of researchers from Brigham and Women’s Hospital in Boston, MA, decided to approach this issue from a different angle – by conducting experiments to identify a better way of targeting beta-amyloid. Their goal was to develop a more efficient antibody to be used in Alzheimer’s therapy.

Principal investigator Dominic Walsh and team came up with a novel technique to collect beta-amyloid and to prepare it in the laboratory.

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Dominic Walsh, PH.D.

“Many different efforts are currently underway to find treatments for Alzheimer’s disease, and anti-[beta-amyloid] antibodies are currently the furthest advanced,” says Walsh. “But the question remains: what are the most important forms of [beta-amyloid] to target? Our study points to some interesting answers,” the lead researcher adds, and these answers are now reported in an open access paper published in the journal Nature Communications.”

Beta-amyloid can be found in many forms. At one end of the spectrum, it exists as a single protein, or monomer, which isn’t necessarily toxic.

At the other end, there is the beta-amyloid plaque, in which many beta-amyloid proteins become tangled together. Beta-amyloid plaques are large enough to be observed using a traditional microscope, and they are involved in the development of Alzheimer’s.

In the current study, as well as in a previous one, Walsh and team looked at beta-amyloid structures to identify the ones that are most harmful in the brain.

Typically specialists use synthetic beta-amyloid samples to create a laboratory model of Alzheimer’s disease in the brain. Very few scientists actually collect beta-amyloid from the brains of individuals diagnosed with the disease.

In the current study, Walsh and team focused on finding better a more specific antibody to target the toxic forms of beta-amyloid but not the less harmful forms. To do so, they developed a novel screening test that requires extracting beta-amyloid from brain samples from people with Alzheimer’s. They added these extracts to induced pluripotent stem cell-derived human neurons and observed the ability of the different antibodies to block the toxic effects of the beta-amyloid.

This screening test allowed the team to discover a particular antibody — called “1C22” — that is able to block toxic forms of beta-amyloid more effectively than other antibodies currently being tested in clinical trials.

Walsh explained the implications of their novel screening method:

“We anticipate that this primary screening technique will be useful in the search to identify more potent anti-[beta-amyloid] therapeutics in the future.”

Using laughter to help find a treatment for Alzheimer’s

Alzheimer's

In 1983, when President Ronald Reagan designated an annual National Alzheimer’s Disease Awareness Month fewer than two million Americans had Alzheimer’s. Today, that number is close to 5.5 million and estimates suggest it will rise to 16 million by 2050. There are no treatments. No cure. But around the globe people are working hard to change that.

At CIRM we have invested more than $60 million in 21 projects aimed at developing a deeper understanding of the disease and, we hope, one day developing effective treatments.

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Lauren Miller Rogen

One of those helping lead that fight is our Board member Lauren Miller Rogen. Lauren has a family history of the disease and uses that to fuel her activism not just on our Board but through Hilarity for Charity, the organization she co-founded with her husband, Seth Rogen.

Lauren was recently profiled by the stem cell advocacy group Americans for Cures, talking about the impact the disease has had on her family, her advocacy on behalf of families struggling to cope with the disease and why she feels humor is such a powerful tool to raise awareness and hope in the fight against Alzheimer’s.

It’s a great interview and you can read it here.

Friday Stem Cell Round: Ask the Expert Facebook Live, Old Brain Cells Reveal Insights and Synthetic Development

Stem Cell Photo of the Week: We’re Live on Facebook Live!

Our stem cell photo of the week is a screenshot from yesterday’s Facebook Live event: “Ask the Expert: Stem Cells and Stroke”. It was our first foray into Facebook Live and, dare I say, it was a success with over 150 comments and 4,500 views during the live broadcast.

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Screen shot of yesterday’s Facebook Live event. Panelists included (from top left going clockwise): Sonia Coontz, Kevin McCormack, Gary Steinberg, MD, PhD and Lila Collins, PhD.

Our panel included Dr. Gary Steinberg, MD, PhD, the Chair of Neurosurgery at Stanford University, who talked about promising clinical trial results testing a stem cell-based treatment for stroke. Lila Collins, PhD, a Senior Science Officer here at CIRM, provided a big picture overview of the latest progress in stem cell therapies for stroke. Sonia Coontz, a patient of Dr. Steinberg’s, also joined the live broadcast. She suffered a devastating stroke several years ago and made a remarkable recovery after getting a stem cell therapy. She had an amazing story to tell. And Kevin McCormack, CIRM’s Senior Director of Public Communications, moderated the discussion.

Did you miss the Facebook Live event? Not to worry. You can watch it on-demand on our Facebook Page.

What other disease areas would you like us to discuss? We plan to have these Ask the Expert shows on a regular basis so let us know by commenting here or emailing us at info@cirm.ca.gov!

Brain cells’ energy “factories” may be to blame for age-related disease

Salk Institute researchers published results this week that shed new light on why the brains of older individuals may be more prone to neurodegenerative diseases like Parkinson’s and Alzheimer’s. To make this discovery, the team applied a technique they devised back in 2015 which directly converts skin cells into brain cells, aka neurons. The method skips the typical intermediate step of reprogramming the skin cells into induced pluripotent stem cells (iPSCs).

They collected skin samples from people ranging in age from 0 to 89 and generated neurons from each. With these cells in hand, the researchers then examined how increased age affects the neurons’ mitochondria, the structures responsible for producing a cell’s energy needs. Previous studies have shown a connection between faulty mitochondria and age-related disease.

While the age of the skin cells had no bearing on the health of the mitochondria, it was a different story once they were converted into neurons. The mitochondria in neurons derived from older individuals clearly showed signs of deterioration and produced less energy.

Aged-mitochondria-green-in-old-neurons-gray-appear-mostly-as-small-punctate-dots-rather-than-a-large-interconnected-network-300x301

Aged mitochondria (green) in old neurons (gray) appear mostly as small punctate dots rather than a large interconnected network. Credit: Salk Institute.

The researchers think this stark difference in the impact of age on skin cells vs. neurons may occur because neurons have higher energy needs. So, the effects of old age on mitochondria only become apparent in the neurons. In a press release, Salk scientist Jerome Mertens explained the result using a great analogy:

“If you have an old car with a bad engine that sits in your garage every day, it doesn’t matter. But if you’re commuting with that car, the engine becomes a big problem.”

The team is now eager to use this method to examine mitochondrial function in neurons derived from Alzheimer’s and Parkinson’s patient skin samples and compared them with skin-derived neurons from similarly-aged, healthy individuals.

The study, funded in part by CIRM, was published in Cell Reports.

“Synthetically” Programming embryo development

One of the most intriguing, most fundamental questions in biology is how an embryo, basically a non-descript ball of cells, turns into a complex animal with eyes, a brain, a heart, etc. A deep understanding of this process will help researchers who aim to rebuild damaged or diseased organs for patients in need.

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Researchers programmed cells to self-assemble into complex structures such as this one with three differently colored layers. Credit: Wendell Lim/UCSF

A fascinating report published this week describes a system that allows researchers to program cells to self-organize into three-dimensional structures that mimic those seen during early development. The study applied a customizable, synthetic signaling molecule called synNotch developed in the Wendell Lim’s UCSF lab by co-author Kole Roybal, PhD, now an assistant professor of microbiology and immunology at UCSF, and Leonardo Morsut, PhD, now an assistant professor of stem cell biology and regenerative medicine at the University of Southern California.

A UCSF press release by Nick Weiler describes how synNotch was used:

“The researchers engineered cells to respond to specific signals from neighboring cells by producing Velcro-like adhesion molecules called cadherins as well as fluorescent marker proteins. Remarkably, just a few simple forms of collective cell communication were sufficient to cause ensembles of cells to change color and self-organize into multi-layered structures akin to simple organisms or developing tissues.”

Senior author Wendell Lim also explained how this system could overcome the challenges facing those aiming to build organs via 3D bioprinting technologies:

“People talk about 3D-printing organs, but that is really quite different from how biology builds tissues. Imagine if you had to build a human by meticulously placing every cell just where it needs to be and gluing it in place. It’s equally hard to imagine how you would print a complete organ, then make sure it was hooked up properly to the bloodstream and the rest of the body. The beauty of self-organizing systems is that they are autonomous and compactly encoded. You put in one or a few cells, and they grow and organize, taking care of the microscopic details themselves.”

Study was published in Science.

Building a better brain organoid

One of the reasons why it’s so hard to develop treatments for problems in the brain – things like Alzheimer’s, autism and schizophrenia – is that you can’t do an autopsy of a living brain to see what’s going wrong. People tend to object. To get around that, scientists have used stem cells to create models of what’s happening inside the brain. They’re good, but they have their limitations. Now a team at the Salk Institute for Biological Studies has found a way to create a better brain model, and hopefully a faster route to developing new treatments.

For a few years now, scientists have been able to take skin cells from patients with neurodegenerative disorders and turn them into neurons, the kind of brain cell affected by these different diseases. They grow these cells in the lab and turn them into clusters of cells, so-called brain “organoids”, to help us better understand what’s happening inside the brain and even allow us to test medications on them to see if those treatments can help ease some symptoms.

Human-organoid-tissue-green-grafted-into-mouse-tissue.-Neurons-are-labeled-with-red-dye.

Human organoid tissue (green) grafted into mouse tissue. Neurons are labeled with red. Credit: Salk Institute

But those models don’t really capture the complexity of our brains – how could they – and so only offer a glimpse into what’s happening inside our skulls.

Now the team at Salk have developed a way of transplanting these organoids into mouse brains, giving them access to oxygen and nutrients that can help them not only survive longer but also display more of the characteristics found in the human brain.

In a news release, CIRM Grantee and professor at Salk’s Laboratory of Genetics, Rusty Gage said this new approach gives researchers a powerful new tool:

“This work brings us one step closer to a more faithful, functional representation of the human brain and could help us design better therapies for neurological and psychiatric diseases.”

The transplanted human brain organoids showed plenty of signs that they were becoming engrafted in the mouse brain:

  • They had blood vessels form in them and blood flowing through them
  • They formed neurons
  • They formed other brain support cells called astrocytes

They also used a series of imaging techniques to confirm that the neurons in the organoid were not just connecting but also sending signals, in essence, communicating with each other.

Abed AlFattah Mansour, a Salk research associate and the paper’s first author, says this is a big accomplishment.

“We saw infiltration of blood vessels into the organoid and supplying it with blood, which was exciting because it’s perhaps the ticket for organoids’ long-term survival. This indicates that the increased blood supply not only helped the organoid to stay healthy longer, but also enabled it to achieve a level of neurological complexity that will help us better understand brain disease.”

A better understanding of what’s going wrong is a key step in being able to develop new treatments to fix the problem.

The study is published in the journal Nature Biotechnology.

CIRM has a double reason to celebrate this work. Not only is the team leader, Rusty Gage, a CIRM grantee but one of the Salk team, Sarah Fernandes, is a former intern in the CIRM Bridges to Stem Cell Research program.

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From left: Sarah Fernandes, Daphne Quang, Stephen Johnston, Sarah Parylak, Rusty Gage, Abed AlFattah Mansour, Hao Li Credit: Salk Institute